Cannabis has been used as a medicinal agent for thousands of years leading to a large amount of research into the active components (the cannabinoids) and their receptors. Two types of cannabinoid receptors have recently been cloned and characterised. The canabinoid CB1 receptor is located primarily in the central nervous system, but is also expressed by peripheral neurones and to a lower extent in other peripheral tissues. On the other hand the cannabinoid CB2 receptor is mostly located in immune cells (Howlett A. C. et al., Pharmacol Rev. 2002, 54, 161-202). The background art of cannabinoid receptors and their ligands has been recently described in Hertzog D. L., Expert Opinion on Therapeutic Patents, 2004, 14, 1435-1452.
Several CB1 receptor antagonists are known in the art. These compounds have been indicated to be useful in a variety of therapeutic applications including the treatment of obesity, nicotine dependence, drug addiction, asthma, liver cirrhosis, psychosis and memory and cognitive disorders (see Lange J. H. M. and Kruse C. G., Current Opinion in Drug Discovery and Development, 2004, 7, 498-506 for a recent review). In common with many cannabinoid ligands, the known compounds are lipophilic entities with relatively low water solubility. There remains a need for further CB1 receptor antagonists which are safe and effective.
Recently indole-2-carboxamide derivatives were generically described in WO/0158869 (Bristol-Myers Squibb) as being active modulators of the cannabinoid receptor and as such useful in the treatment of respiratory diseases. WO/0158869, however, makes no specific disclosures of any 1-benzyl-indole-2-carboxamide derivatives.